Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-04-01 Epub Date: 2024-02-23 DOI:10.1007/s40262-024-01350-x
Brit S Rohr, Evelyn Krohmer, Kathrin I Foerster, Jürgen Burhenne, Martin Schulz, Antje Blank, Gerd Mikus, Walter E Haefeli
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引用次数: 0

Abstract

Background: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed.

Methods: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses.

Results: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined.

Conclusion: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation.

Clinical trial registration: EudraCT number: 2021-006643-39.

Abstract Image

健康志愿者口服短期利托那韦与三种 Xa 因子抑制剂的相互作用以及 CYP2D6、CYP2C19 和 CYP3A4 活性的时间过程
背景:我们研究了5天低剂量利托那韦治疗对三种Xa因子抑制剂(FXaI)药代动力学的影响。同时,还评估了细胞色素 P450 (CYP) 3A4、2C19 和 2D6 活性的时间进程:在一项开放标签、固定顺序的临床试验中,对八名健康志愿者口服五天利托那韦(100 毫克,每天两次)对三种口服微剂量 FXaI(利伐沙班 25 微克、阿哌沙班 25 微克和埃多沙班 50 微克)和微剂量探查药物(咪达唑仑 25 微克、育亨宾 50 微克和奥美拉唑 100 微克)药代动力学的影响和持续时间进行了评估。所有药物的血浆浓度均采用经过验证的液相色谱-串联质谱(LC-MS/MS)方法进行定量,药代动力学则采用非室分析方法进行分析:利托那韦增加了阿哌沙班、依度沙班和利伐沙班的暴露量,但在不同程度上增加了血浆浓度-时间曲线下的观察面积(几何平均比分别为 1.29、1.46 和 1.87)。在利托那韦用药 2 天后,观察到强烈的 CYP3A4 抑制(几何平均比值大于 10)和中度的 CYP2C19 诱导(0.64),CYP2D6 没有变化。CYP3A4 的恢复半衰期为 2.3 天:这项使用三种微剂量 FXaI 的试验表明,利伐沙班的剂量最多只能在短期利托那韦治疗期间减少,而且只能在接受高剂量维持治疗的患者中减少。彻底的时间序列分析表明,随着时间的推移,对三种不同的药物代谢酶产生了不同的影响,CYP3A4立即受到严重抑制,停药后才缓慢恢复:临床试验注册:EudraCT 编号:2021-006643-39。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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